Fibrosis is the abnormal formation of excess fibrous connective tissue in an organ or tissue. Fibrosis is a significant cause of patient morbidity and mortality when it occurs in lung and other organs. This can be seen in the interstitial lung diseases (ILD), including idiopathic pulmonary fibrosis (IPF), scleroderma, radiation-induced pulmonary fibrosis and bleomycin lung, where fibroproliferative matrix molecule deposition, enhanced collagen accumulation, apoptosis and alveolar septal rupture with honeycombing are often juxtaposed and can lead to fatal consequences (Noble et al., 2004, Clin Chest Med. 25:749-758, vii.; Raghu 1998, Interstitial lung disease: a clinical overview and general approach. In Fishman's Pulmonary Diseases and Disorders. Fishman et al., eds., Mc-Graw Hill Inc., N.Y., N.Y. 1037-1053; Selman et al., 2004, Drugs 64:405-430; Thannickal et al., 2006, Proc Am Thorac Soc. 3:350-356). Airway fibrosis is also an important contributor to the pathogenesis of airways disorders such as bronchiolitis obliterans syndrome and asthma (Elias et al., 2003, J Clin Invest. 111:291-297; Elias et al., 1999, J Clin Invest. 104:1001-1006; Hamid, 2003, J Allergy Clin Immunol. 111:1420-1421; Pendergast, 2002, AdvCancer Res. 85:51-100; Vignola et al., 2003, Chest 123:417 S-422S). The mechanisms of tissue fibrosis in these important lung disorders are poorly understood.
The transforming growth factor-beta1 (TGF-β1) has been implicated in the pathogenesis of a variety of fibrotic disorders including IPF, scleroderma, radiation induced pulmonary fibrosis and asthma (Leask et al., 2004, FASEB J. 18:816-827; Bergeron et al., 2003, Eur Respir J. 22:69-76; Boxall et al., 2006, Eur Respir J. 27:208-229; Howell et al., 2006, Curr Drug Targets 7:547-565; Khalil et al., 1996, Am J Respir Cell Mol. Biol. 14:131-138; Khalil et al., 2001, Thorax 56:907-915; Martin et al., 2000, Int J Radiat Oncol Biol Phys. 47:277-290; Steen, 2006, Autoimmun Rev. 5:122-124). The TGF-β1 family proteins are multi-functional cytokines that play pivotal roles in diverse biologic processes including the regulation of cell growth and survival, cell and tissue differentiation, development, inflammation, immunity, hematopoiesis and tissue remodeling (Leask et al., 2004, supra). TGF-β1 is essential for wound healing and stimulates matrix molecule deposition. The important roles that TGF-β1 might play in IPF can be seen in human studies that demonstrated that bioactive TGF-β1 is expressed in an exaggerated fashion in lungs from patients with IPF (Khalil et al., 1996, supra; Khalil et al., 2001, supra; Daniels et al., 2004, J Clin Invest. 114:1308-1316; Xu et al., 2003, Am J. Physiol Lung Cell Mol. Physiol. 285:L527-539). Animals studies have also demonstrated that TGF-β1 is a critical mediator of bleomycin-induced pulmonary fibrosis (Daniels et al., 2004, supra; Nakao et al., 1999, J Clin Invest. 104:5-11; Yehualaeshet et al., 2000, Am J Respir Cell Mol. Biol. 23:204-212) and that high dose adenoviral transfer of TGF-β1 causes a progressive fibrotic response in the lung in vivo and an IPF-like disease with fibroblastic foci in an explant culture system (Xu et al., 2003, supra). The mechanisms that TGF-β1 uses to mediate these tissue responses, however, have not been adequately defined.
The semaphorins (SEMA) are a large family of phylogenetically conserved, secreted and membrane bound proteins that are divided into eight classes based on sequence similarities and distinct structural features (Pasterkamp et al., 2003a, Curr Opin Neurobiol. 13:79-89; Pasterkamp et al., 2003b, Nature 424:398-405). Members of this family act as axon guidance molecules, and SEMA abnormalities have been implicated in the pathogenesis of neurologic disorders such as Alzheimer's and motor neuron degeneration (Pasterkamp et al., 2003a, supra; Pasterkamp et al., 2003b, supra). SEMA are also expressed on myeloid and lymphoid cells including B cells, T cells, NK cells and macrophages and have been implicated in immune responses and the regulation of organogenesis, angiogenesis, apoptosis and neoplasia (Pasterkamp et al., 2003a, supra; Pasterkamp et al., 2003b, supra; Czopik et al., 2006, Immunity 24:591-600; Delorme et al., 2005, Biol Cell 97:589-597; Holmes et al., 2002, Scand J. Immunol. 56:270-275).
SEMA 7A, also called CDw108, was originally discovered based on sequence similarities with the vaccinia virus SEMA homologue A39R and is now known to be the homolog of a number of viral semaphorins (Comeau et al., 1998, Immunity 8:473-482; Comeau et al., 1998, Immunity 8:473-482; Xu et al., 1998, J Biol. Chem. 273:22428-22434; Lange et al., 1998, Genomics 51:340-350; Delorme et al., 2005, supra). SEMA 7A is unique amongst SEMA because it is stabilized via a glycosylphosphatidylinositol (GPI) membrane linkage (Pasterkamp et al., 2003a, supra; Pasterkamp et al., 2003b, supra; Czopik et al., 2006, supra; Xu et al., 1998, supra). In addition, unlike many SEMA, which act as repulsive axonal guidance clues, SEMA 7A enhances central and peripheral axonal growth and is required for proper axon track formation during embryonic development (Pasterkamp et al., 2003a, supra; Pasterkamp et al., 2003b, supra). SEMA 7A may also play prominent roles in inflammation, immunity and dental and osseous tissue responses based on its ability to stimulate macrophage chemotaxis and cytokine production and inhibit T cell function and its expression on ondontoblasts, stimulation of osteoblast migration and regulation of osteoclast fusion (Czopik et al., 2006, supra; Delorme et al., 2005, supra; Holmes et al., 2002, supra; Moresco et al., 2005, J. Neurosci. 25:6105-6118). The effects of SEMA 7A are thought to be mediated via at least two receptors, plexin C1 and beta1 integrin subunits (Pendergast, 2002, Adv Cancer Res. 85:51-100; Pasterkamp et al., 2003b, supra; Delorme et al., 2005, supra). To date, there is no evidence that SEMA 7A play a pathogenic role in fibrosis.
There exists a need for a better molecular understanding of tissue fibrosis in general, and in pulmonary disorders in particular. Further, there is a need in the art for a therapy for treating or alleviating fibrosis. The present invention addresses and meets these needs.